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Cingulin, Paracingulin, and PLEKHA7: Signaling and Cytoskeletal Adaptors at the Apical Junctional Complex

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Cingulin, Paracingulin, and PLEKHA7: Signaling and Cytoskeletal Adaptors at the Apical Junctional Complex Ann. N.Y. Acad. Sci. ISSN 0077-8923 ANNALS OF THE NEW YORK ACADEMY OF SCIENCES Issue: Barriers and Channels Formed by Tight Junction Proteins Cingulin, paracingulin, and PLEKHA7: signaling and cytoskeletal adaptors at the apical junctional complex Sandra Citi, Pamela Pulimeno, and Serge Paschoud Department of Molecular Biology, University of Geneva, Geneva, Switzerland Address for correspondence: Sandra Citi, Department of Molecular Biology, 4 Boulevard d’Yvoy, 1211–4 Geneva, Switzerland. [email protected] Cingulin, paracingulin, and PLEKHA7 are proteins localized in the cytoplasmic region of the apical junctional complex of vertebrate epithelial cells. Cingulin has been detected at tight junctions (TJs), whereas paracingulin has been detected at both TJs and adherens junctions (AJs) and PLEKHA7 has been detected at AJs. One function of cingulin and paracingulin is to regulate the activity of Rho family GTPases at junctions through their direct interaction with guanidine exchange factors of RhoA and Rac1. Cingulin also contributes to the regulation of transcription of several genes in different types of cultured cells, in part through its ability to modulate RhoA activity. PLEKHA7, together with paracingulin, is part of a protein complex that links E-cadherin to the microtubule cytoskeleton at AJs. In this paper, we review the current knowledge about these proteins, including their discovery, the characterization of their expression, localization, structure, molecular interactions, and their roles in different developmental and disease model systems. Keywords: cingulin; paracingulin; PLEKHA7; ZO-1; p120ctn; junctions features of TJs, confirming that TJ proteins, together Cingulin and paracingulin with AJ proteins, can be part of atypical junctional Cingulin was discovered as a Mr 140 kDa pro- structures. tein that copurified with myosin II from intesti- The sequence of cingulin, its biochemical behav- nal epithelial cells and was localized in an apical ior, and rotary shadowing electron microscopy show circumferential “belt” in these cells1—hence the that the molecule exists as a parallel homodimer of name cingulin, from the Latin cingere (to form a two subunits, each comprising a globular head do- belt around). Immunoelectron microscopy demon- main, a coiled-coil “rod,” and a small globular tail strated that cingulin is localized at the cytoplasmic (Fig. 1).10,11 Although such domain organization is surface of tight junctions (TJs) in intestinal epithe- similar to that of myosin II, the sequence of cingulin lial cells.1,2 Furthermore, the subcellular localization does not indicate either the presence of an actin- and tissue distribution of cingulin indicate a close activated MgATPase activity or a propensity of the correlation with the continuous TJ belt of differen- coiled-coil rod to form higher order multimolecular tiated epithelia2–4 and endothelia,2,5 as well as the assemblies, such as myosin.11 Cingulin binds to and continuous and discontinuous junctions of strat- bundles actin filaments in vitro and also interacts ified epithelia.2,6,7 Interestingly, expression of cin- in vitro with myosin, suggesting that it could link gulin can be induced in fibroblasts by differentiating TJ proteins to the actin cytoskeleton.10,12 However, agents, resulting in its targeting to spot-like adherens since no major changes in the organization of the junctions (AJs).8 Moreover, cingulin is detectable at actincytoskeletonhavebeendetectedincingulin- sites, such as the kidney glomerular slit diaphragms9 depleted cells, it seems that cingulin does not play and the outer limiting membrane of the retina,2 a significant role in controlling the architecture of which do not have the characteristic morphological actin filaments. doi: 10.1111/j.1749-6632.2012.06506.x Ann. N.Y. Acad. Sci. 1257 (2012) 125–132 c 2012 New York Academy of Sciences. 125 Cingulin, paracingulin, and PLEKHA7 Citi et al. Figure 1. A molecular machinery linking TJs to AJs. Simplified diagram representing the molecular interactions between cingulin (CGN), paracingulin (CGNL1), PLEKHA7, the TJ protein ZO-1, and the AJ protein p120ctn. The TJ and AJ domains of the plasma membrane are represented on the left, with schematics of JAM-A (purple) and claudins/occludin (blue) at TJs and E-cadherin (blue) at AJs. The major structural domains of the proteins are illustrated by colored boxes, whereas the regions involved in mutual interactions are highlighted by red rectangles, linked by lines with arrows. The head and rod domains are shown for CGN and CGNL1, with the ZIM (ZO-1–interaction motif) regions in the N-terminal part of the head,16,30 and the PLEKHA7-interacting region C-terminal to the ZIM in CGNL1.16 Dotted lines above the schemes of CGN and CGNL1 indicate the regions that interact with GEFs in vitro.21,22,27 ZO-1 contains PDZ domains that mediate the interaction with transmembrane proteins, Src homology 3 (SH3), guanylate kinase (GUK), and actin-binding-region (ABR) domains.33 The CGN- and CGNL1-binding region of ZO-1, as identified by yeast two-hybrid screens, is composed within the region C-terminal to the ABR. The CGNL1- and p120ctn-interacting regions of PLEKHA7 are distinct and located in the central region of the molecule. p120ctn contains a central region with armadillo (ARM) repeats. Afadin is another key component of the apical AJ belt but has been omitted from this scheme for the sake of clarity. [Correction added July 17, 2012 after online publication: Figure has been changed to show the correct dotted lines above the scheme of CGN] Paracingulin (Mr 150–160 kDa) is likely to be rescence shows junctional and apical localizations, a paralogue of cingulin—e.g., the two proteins whereas immunoelectron microscopy shows an ex- probably arose from a gene duplication event clusive TJ localization. Furthermore, in intestinal and hence the name “para”-cingulin.13,14 Cingulin tissue, paracingulin is associated with nonjunctional and paracingulin show a good degree of sequence actin filaments in the basal region of the cells.15 homology, especially in the coiled-coil rod do- A nonjunctional localization of paracingulin along main (39% identity) and in the N-terminal ZO-1– actin stress fibers has also been observed in fibrob- interacting motif (ZIM; 73% identity; Fig. 1).13,15,16 lasts expressing exogenous paracingulin.15,16 There- Thus, we speculate that paracingulin also exists as fore, although the actin- and myosin-binding prop- a parallel dimer. The head region of paracingulin erties of paracingulin are not known, paracingulin is larger than the head domain of cingulin (ap- may have a more direct association with the actin proximately 600 versus approximately 350 residues, cytoskeleton than cingulin. depending on species), and the coiled-coil rod is Unlike cingulin, paracingulin is structurally smaller (approximately 660 residues versus approx- linked to the microtubule cytoskeleton. Perturb- imately 800), accounting for the difference in their ing the organization of microtubules results in apparent molecular size. Paracingulin was inde- loss of junctional paracingulin, whereas cingulin pendently characterized as a junction-associated is unaffected.14 This is probably due to the inter- coiled-coil protein (JACOP).15 Immunoelectron action of paracingulin with PLEKHA7,16 which is microscopy analysis showed that unlike cingulin, indirectly bound to microtubules17 (see later). In the localization of paracingulin is more promiscu- contrast, both cingulin and paracingulin localiza- ous. In kidney tissue, where paracingulin mRNA tions are dramatically affected by actin filament- is detected at high levels, paracingulin is localized disrupting drugs,14 confirming the association of both at TJs and AJs.15 In liver tissue, immunofluo- both proteins with the actin cytoskeleton. Indeed, 126 Ann. N.Y. Acad. Sci. 1257 (2012) 125–132 c 2012 New York Academy of Sciences. Citi et al. Cingulin, paracingulin, and PLEKHA7 the dynamics of junction exchange of cingulin and of cingulin does not have any detectable effect on paracingulin are similar to actin and more rapid junction assembly and development of the TJ bar- than those of ZO-1.14 Cingulin and paracingulin rier in kidney cells, and the junctional targeting and can be detected in a complex together, and with activity of p114RhoGEF in these cells depends on otherTJproteins.14,16 However, since the junctional the FERM domain–containing protein Lulu2, rather recruitment and dynamics of cingulin are indepen- than cingulin.24 dent of paracingulin and vice-versa, the two pro- Significantly, the increase in cell proliferation, teins likely do not function as a unit, but rather cell density at confluence, and claudin-2 expres- as independent proteins, with partially redundant sion in cingulin-depleted kidney epithelial cells are functions.14 rescued by the inhibition of RhoA, indicating that In summary, cingulin and paracingulin are struc- RhoA mediates, at least in part, the effects of cin- turally homologous proteins, with an asymmetric gulin on transcriptional and cell cycle regulation.22 shape, similar dynamics, partially overlapping sub- It is important to note that RhoA is modulated by cellular localizations, and distinct interactions with several other junctional molecules,25 and that tran- the actin and microtubule cytoskeletons. scription factors such as ZONAB and YAP are pu- tative downstream effectors of RhoA.26 Therefore, Cingulin and paracingulin as adaptors for the activity of cingulin as a RhoA regulator must guanidine exchange factors
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